1. Field of the Invention
The present disclosure relates to the use of pharmaceutical agents to manipulate serotonin in animal mammary glands. Use of the serotonin agents results in increased PTHrP levels, resulting in the release of calcium from the bone, which improves lactation.
2. Description of the Related Art
The transition from pregnancy to lactation in mammals is a critical period for calcium homeostasis. Approximately 5% of all dairy animals experience severe periparturient hypocalcemia, also known as milk fever. This number increases to approximately 50% in older cows, and the highest-producing cows are at highest risk of this pathology. At calving, there is a 4-5% increase in plasma calcium clearance, with calcium replacement coming from the mobilization of calcium from bone. Similar bone calcium mobilization occurs in human women during the periparturient period.
The specific mobilization of bone in lactation is driven by a hormone named “Parathyroid Hormone-related Protein (PTHrP, gene symbol PTHLH, also known as HHM; PLP; BDE2; PTHR; PTHRP).” A failure to maintain calcium homeostasis during the transition to milk secretion is at the heart of periparturient hypocalcemia.
PTHrP was originally discovered as the factor responsible for humoral hypercalcemia of malignancy, and is secreted from a variety of advanced soft tissue cancers. The N-terminal portion of PTHrP is similar to parathyroid hormone (PTH), and acts via the type 1 PTH receptors (PTH1R) to induce the receptor-activator of NFKB ligand (RANKL).
PTHrP is undetectable in the circulation except during lactation, in advanced metastatic disease, or in patients with hyperprolactinemia. In spite of obvious correlations with states of elevated prolactin (PRL), PRL did not induce PTHrP in conventional cell cultures of mammary epithelium, and our lab has done numerous experiments that confirmed that PRL does not induce PTHrP in mammary cells by a direct mechanism.
A previous study showed that serotonin (5-HT) induced PTHrP expression in vascular smooth muscle cells. In the mammary glands 5-HT regulates key aspects of epithelial homeostasis by autocrine-paracrine signaling. The processes regulated by 5-HT include not only specialized mammary gland functions such as milk protein and milk lipid biogenesis, but also fundamental cell biological processes (i.e., apoptosis, barrier permeability, cell shedding). Epithelia lining other ductal/alveolar secretory organs also possess local 5-HT signaling systems, which have been implicated in various aspects of epithelial homeostasis.
It has now been shown that serotonin, synthesized within the mammary gland, is responsible for causing the increase in PTHrP associated with the onset of lactation. Consequently, drugs that increase serotonin signaling are useful for maintaining healthy calcium levels in lactating females.